Breast cancer accounts for more than 20% of newly diagnosed cancers for women worldwide. After initial diagnosis, neoadjuvant chemotherapy (NAC) is often administrated with one or more anti-neoplastic drugs to treat locally advanced breast cancer. Depending on the treatment regimen, many patients do not benefit from NAC and thus receive toxic drugs and suffer their side effects. If these patients are identified early, they will have the option of avoiding further administration of these agents and seeking alternative treatment or early surgery.
The gold standard of assessing NAC response is by histopathological examination of tumor specimens. Other forms of treatment monitoring include physical examination, mammography and ultrasound. An examination via magnetic resonance imaging (MRI), with its inherent multi-modal nature, has emerged as a platform of choice to provide several quantifiable biomarkers to monitor tissue changes during NAC. So far, frequently used magnetic resonance (MR) modalities include dynamic contrast-enhanced (DCE) MRI, diffusion-weighted imaging (DWI) and magnetic resonance spectroscopy (MRS). DCE-MRI relies on an injection of an intravenous contrast agent and continuous acquisitions of T1-weighted images as the agent perfuses into and out of a region of interest (e.g., a tumor locus). As this method has shown great sensitivity, it has become a central component of the standard-of-care breast MRI exam. However, other MR-based metrics relying on endogenous tissue contrasts are still in varying stages of technical or clinical development, specifically DWI, MRS, and amide proton transfer (APT) imaging.
DWI measures the rate of water molecules' random translation in the form of the apparent diffusion coefficient (ADC). ADC has been shown to indicate cell membrane integrity and tumor cell density. Treatment induced loss of tumor cells and increase of the extracellular space has been linked to higher ADC values during treatment. An early increase in ADC in locally advanced breast cancer may be a valuable predictor of positive outcome of NAC. Conversely, a decrease in ADC can identify non-responders. Further, Choline's role as a biomarker for cell membrane turnover has been investigated and in vivo MRS measurements of Choline and other Choline containing compounds (i.e., Choline metabolites) reflect proliferative activity of malignant cells that results in higher membrane components and elevated signals from total Choline (tCho). Early changes of tCho have been reported to occur 24 hours after the first cycle of NAC. Although general agreement has been reached regarding the usage of ADC and tCho in well-controlled clinical trials, the reliability and accuracy of these measurements are still not well established and have therefore prevented their widespread adoption in the mainstream standard-of-care setting.
APT imaging relies on a contrast generated by chemical exchange saturation transfer (CEST). Specifically, the targeted amide resonance of mobile proteins and peptides at 8.3 ppm can exchange with water protons at 4.7 ppm. Although direct observation of the amide resonance is possible, a more sensitive mechanism is to apply RF irradiation to saturate this resonance and let the saturated protons exchange with water protons. As the exchange is a continuous process, a sustained irradiation will result in a measurable decrease in the signal of water protons. The amount of signal decrease is proportional to the density of mobile proteins and peptides and depends as well on tissue pH. Therapy induced reduction of tumor cells and changes in pH should result in changes in the APT measurement. Recently, in n biopsy-proven high grade gliomas, APT-weighted images showed consistent hyperintensity even in tumors that did not display enhancement after administering a gadolinium based contrast agent. Low-grade gliomas showed iso-intensity or scattered hyperintensity, significantly lower than high-grade tumors. Additionally, APT imaging has been developed and applied in a pre-clinical study to evaluate the response to radiation therapy. Those results showed hyperintense signal with active glioma and hypointense or isointense with radiation necrosis. In summary, these early studies demonstrate APT contrast as a promising biomarker that is directly linked to the malignancy and density of tumor cells.